DiGeorge syndrome type 1 (DGS1) is estimated to be the most prevalent inheritable genetic deletion syndrome, occurring in 1 per 4,000 live births. A large range of clinical characteristics characterizes this autosomal dominant disease, including congenital heart defects, velopharyngeal abnormalities, learning difficulties, endocrine abnormalities, renal anomalies, and immune defects. Unfortunately the diagnosis of DiGeorge syndrome is delayed in most individuals because of this varying clinical phenotype, as well as the fact that the diagnostic cytogenetic fluorescent in situ hybridization (FISH) probe misses at least 15% of all microdeletions in the DGS1 region (chromosome 22q11.2). As a result, it is estimated that only 25% of DGS1 patients are diagnosed in infancy, with the median age of diagnosis for all other DGS1 patients being 8 years of age. Early diagnosis and appropriate medical intervention can prevent and effectively treat many of the co-morbidities associated with DGS1. Therefore, there is a critical need to develop a more sensitive and cost-effective screening method for DGS1. We hypothesize that data generated from recently developed high-density single-nucleotide polymorphism (SNP) genotype arrays will allow the development of effective screening tests for DGS1. The Aims of this study will focus on 2 areas: Aim 1 will focus on accurately defining the deletion boundries and segments found in the majority DGS1 subjects using high-density SNP arrays, and demonstrate that standard FISH cytogenetics misses a larger fraction of DGS1 subjects than previously appreciated. Aim 2 will focus on the development a highly sensitive and cost- effective screening test that can be subsequently implemented into a State Newborn Screening Program for DGS1. PUBLIC HEALTH RELEVANCE: We believe this proposal fits well with the overall mission statement of the NIH "to extend healthy life and reduce the burdens of illness and disability." Specifically, our proposal fulfills the NIH roadmap of 1) supporting projects that transform and extend our understanding of genetic disorders, 2) offering potential immediate and long-term translational benefit to the health of individuals, and 3) promoting unique partnerships - in our case, research between scientists and physician-scientists at CHW/MCW and scientists at the Wisconsin State Laboratory of Hygiene. There are two main goals of our proposal. The first goal is to acquire long-term clinical and genetic information of the most common genetic deletion known (DiGeorge syndrome;DGS), affecting 1 in 4,000 live births in the state. This information will allow us to better detect and effectively treat the multiple co-morbidities associated with DGS. Our second goal, and the main purpose of our proposal, is the successful development of a sensitive and cost-effective newborn screen for DGS that could be applied to State Newborn Screening Programs. This is an important goal since the majority of DGS subjects go undiagnosed or misdiagnosed, and subsequently suffer from untreated co- morbidities associated with DGS. We strongly believe that by detecting DGS subjects early in life, it will allow for proper and potentially life-saving medical interventions for the many disabilities associated with DGS, such as congenital heart disease and severe immunodeficiency.